Treatment with a sphingosine-1-phosphate analog inhibits airway remodeling following repeated allergen exposure

Abstract

Sphingosine-1-phosphate (S1P) is an immunomodulatory lipid mediator that plays an important role in lymphocyte trafficking. Elevated levels of S1P are found in bronchoalveolar lavage (BAL) fluid of patients with asthma; however, its role in disease is not known. FTY720, a synthetic analog of S1P, has been shown to abrogate allergic inflammation and airway hyperresponsiveness following acute allergen challenge. However, its effects on asthmatic airway remodeling induced by repeated allergen exposure are unknown. Ovalbumin (OVA)-sensitized rats were challenged on days 14, 19, and 24 after sensitization. FTY720 or vehicle (PBS) therapy was administered 1 h prior to each challenge. BAL fluid and quantitative histological analysis were performed 48 h after the last challenge. FTY720 inhibited OVA-induced features of airway remodeling including increased airway smooth muscle mass and bronchial neovascularization, without affecting lymphocyte numbers in secondary lymphoid organs. Furthermore, CD3+ cells adjacent to airway smooth muscle bundles were increased in OVA-challenged rats but the increase was inhibited by FTY720. There was an expansion of bronchus-associated lymphoid tissue following FTY720 treatment of OVA-challenged animals. Real-time quantitative PCR revealed that Th2-associated transcription factors were inhibited following FTY720 therapy. Airway remodeling is a cardinal feature of severe asthma. These results demonstrate that allergen-driven airway remodeling can be inhibited by FTY720, offering potential new therapies for the treatment of severe asthma.

Angiogenesis and airway reactivity in asthmatic Brown Norway rats

“…Although our sensitization regimen differed somewhat from the work of others, the range of hyperresponsiveness seen after 3 wks sensitization was comparable to that previously reported in the Brown Norway rat after HDM sensitization [12,31]. Furthermore, baseline airway resistance and the level of reactivity after allergen sensitization was similar to that observed by Karmouty-Quintana who showed concomitant increases in airway vascularity after ovalbumin sensitization [13]. …”

“…Furthermore, several studies have shown that allergen sensitization leads to increased airway vascularity concomitant with enhanced reactivity and inflammation [13,27]. Both ovalbumin and house dust mite have been used to sensitize mice where investigators have reported increased lung vascularity of relatively large pulmonary vessels associated with large airways [8,9,28,29].…”

“…Thus, the use of mice to study allergen-induced angiogenesis as a model for human airway vascular remodeling requires further validation. However, using Brown Norway rats, mammals with an airway vasculature similar to the human, Karmouty-Quintana and colleagues have shown that bronchial angiogenesis develops concomitantly with airway hyperresponsiveness after ovalbumin sensitization [13]. This model provides an important opportunity to further determine the pathophysiology of the angiogenic vasculature.…”

“…All complete airways cut in cross section (max/min diameter ratio <1.5) were sized by measuring the airway basement membrane perimeter (ImageJ) and the number of blood vessels within the associated airway wall were counted. Results were expressed as vessel number normalized to airway perimeter or airway perimeter 2 , which is proportional to airway area and used previously by others [13]. Airways without bronchial vessels were not included.…”

The modulation of large airway smooth muscle phenotype and effects of epidermal growth factor receptor inhibition in the repeatedly allergen-challenged rat

“…The U.S. BN rats also fail to develop AHR (19). We have previously observed differences in the degree of vascular remodeling and inflammation and of expression in Th2 cytokines between U.S. and UK BN rats (15,47). Previous studies of allergen-challenged BN rats have shown that increased ASM mass is attributable to hyperplasia (31,34,45).…”